Citations

Abstract Background: Chimeric antigen receptor T-cell (CAR T) therapies have demonstrated significant clinical efficacy in hematologic malignancies, but have proven challenging in solid tumors, in part owing to a lack of tumor-specific targets and unmanageable toxicity. Mesothelin (MSLN) expression normally is limited to the mesothelium of major body cavities but can be upregulated in diverse solid tumor types (cancer.gov/tcga), making it a potential target for cancer therapy. MSLN-targeted cell therapy approaches, including CAR T and T-cell receptor fusion therapies, have shown promising clinical activity; however, on-target, off-tumor toxicity including fatal events have occurred (Beatty, et al. Gastroenterology. 2018.; Haas, et al. Mol Ther. 2023.; Hong, et al. ESMO 2021. Abstract 9590.). A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs: an activating and blocking receptor. The activator recognizes MSLN present on the surface of both tumor and normal cells; the blocker inhibits the CAR T activator when it binds human leukocyte antigen (HLA)-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 loss of heterozygosity (LOH), the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (Hamburger, et al. Mol Immunol. 2020). Through this unique selective mechanism, A2B694 may provide a therapeutic window to treat patients with MSLN-expressing solid tumors exhibiting HLA-A*02 LOH. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, mesothelioma, or other solid tumors with MSLN expression. Eligible patients must have progressed following standard of care therapy. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), which identifies patients with tumor-associated HLA-A*02 LOH via next-generation sequencing (Tempus AI, Inc). Eligible patients enroll in the BASECAMP-1 study and undergo leukapheresis. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess overall response rate per RECIST v1.1. The first patient was enrolled on EVEREST-2 in April 2024. Dose escalation is ongoing. Citation Format: Julian R. Molina, Antonious Hazim, Oliver Dorigo, Salman R. Punekar, Monica Avila, Diane M. Simeone, Kedar Kirtane, Gottfried E. Konecny, Jeffrey Ward, Matthew Block, Jennifer Specht, Leslie Boyd, Yanyan Lou, Jong Chul Park, Jacqueline D. Xuan, Ramez N. Eskander, Gayanie Ong, Marco Davila, Wendy Langeberg, Marcela Maus, Armen Mardiros, Frederick L. Locke, Andrea Wise, David G. Maloney, John Welch, J. Randolph Hecht. EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod CAR T-cell therapy, in patients with mesothelin-expressing solid tumors with human leukocyte antigen-A*02 loss of heterozygosity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT186.

Abstract Background: Financial toxicity can have devastating long-term effects for cancer patients (pts) and their family members which may impact their access to care, adherence and, ultimately, outcomes. Identifying those at greatest risk is key to mitigating costs and distress to pts. Here we report results from a screening questionnaire on financial risks among Southeast Asian (SE-A) pts. Methods: This retrospective review included pts on the cancer patient registry at Mayo Clinic (Arizona, Florida, Minnesota, Wisconsin, and Iowa) who had completed a clinical visit in an oncology-related department (hematology, medical oncology, radiation oncology, etc) within the past 270 days prior to 6/4/24. Pts completed an electronic social determinant of health questionnaire of which financial risks and transportation needs are the focus of this study: 1) how hard is it for you to pay for the very basics like food, housing, medical care, and heating? 2) in the past 12 months, has lack of transportation kept you from medical appointments or from getting medications. Our primary endpoints include the association between financial risks, active bad debts (defined as having >$5000 owed for high active bad debt, $0-$5000 for some active bad debt), pre-appointment review (PAR) flag status and transportation needs. Descriptive statistics and Chi-square were used to analyze factors associated with financial risks. Results: We identified 81, 731 pts who completed the questionnaire, among whom 387 were SE-A. Compared to non-SE-A and White, 6.5% have some active bad debt vs 3.3% and 3.6% (p<0.001), and 1.0% had high active bad debt vs 0.8% and 0.7% (p<.001); 58.4% had low financial risk vs 60% and 66% (p<0.001) and 2.3% with high risk vs 1.5% and 1.6% (p<0.001), 4.1% declined to answer and 29.7% were unknown. Bad debt was associated with PAR flag (P <0.001) and financial risk (P<0.001). For transportation among SE-A, 2.3% had unmet transportation needs, 1.8% declined/unable to answer, while 17.8% were unknown. Those with transportation needs were associated with active debt and financial risk (p<0.001). Conclusion: In this cohort, we identified SE-A with highest rates of active debt and higher financial risks compared to Non-SE-A and White. A large percentage of patients declined to answer or are unknown. Future pilot questionnaire is in development to identify pts concerns for medical costs, financial strain and the receptivity to be connected to resources/referrals to address them. Citation Format: Nguyen H. Tran, Jordan Mason, Wendy Hanson, Kimberly Steinbert, Minji Lee, Robert McWilliams. Financial risks in southeast asian patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7094.

Abstract Introduction: Breast cancer genome-wide association studies (GWAS) have identified over 200 susceptibility loci, many replicated in diverse populations. However, cross-ancestry evaluation of breast cancer genetic architecture remains limited. We examined breast cancer genetic architecture using GWAS summary results from European (EUR; cases (ca) = 188,474, controls (co) = 96,201), East Asian (EAS; ca = 20,393, co = 86,329), African American (AA; ca = 9,235, co = 10,184), and US Hispanic/Latina and Latin American (H/L; ca = 2,396, co =7,468) studies. Methods: GWAS results were derived from the Breast Cancer Association Consortium, the African Ancestry Breast Cancer Genetics Consortium (AABCG), Biobank Japan, and a meta-analysis of five studies of H/L women with breast cancer. Linkage disequilibrium (LD) scores were generated for EUR, EAS, and AMR using the 1000 Genomes Project, while AA LD scores were derived from a subset of AABCG controls. Heritability was estimated for each ancestry group using LD score regression. Genetic correlations between populations were assessed via Popcorn. Polygenicity was analyzed using GENESIS; however, due to the limited sample size in the H/L studies, these estimates were restricted to AA, EAS, and EUR. Enrichment of heritability across regulatory elements was evaluated using stratified LD score regression across all populations. Results: The logit-scale heritability and corresponding standard error (SE) were 0.466 (0.066) for EAS, 0.501 (0.050) for EUR, 0.588 (0.360) for H/L, and 0.614 (0.095) for AA. The estimated number of independent susceptibility loci was 4,446 for EAS, 5,235 for EUR, and 8,308 for AA. Using a clumping and thresholding approach, an optimal set of common variants were projected to explain 38.6% (EUR), 39.4% (EAS), and 26.2% (AA) of genetic variance for samples of 100,000 cases and 100,000 controls with AUCs from corresponding estimated polygenic risk scores (PRSs) of 0.621 (EUR), 0.634 (EAS), and 0.611 (AA). Genetic correlations were strongest between EUR and EAS (ρ = 0.79, SE = 0.08) and EUR and H/L (ρ = 0.68, SE = 0.21), and weakest between AA and EAS (ρ = 0.42, SE = 0.14) and AA and H/L (ρ = 0.26, SE = 0.24). Among 73 genomic features, we found significant (P < 0.05/73) enrichment in heritability in EUR for ‘ancient promoter’ regions, transcription factor binding sites, H3K4me3, ‘super-enhancers’, H3K4me1, H3K27ac; in EAS for ‘super-enhancers’; and in AA for H3K27ac. No genomic features were significantly enriched in H/L, likely due to limited power. Conclusion: These findings suggest a shared breast cancer genetic architecture across diverse populations, as well as the potential for a similar level of breast cancer risk stratification by PRS in these populations. Expanding GWAS in underrepresented populations is essential to improve genetic risk predictions and foster equitable cancer prevention. Citation Format: James L. Li, Maria Zanti, Jacob Williams, Om Jahagirdar, Guochong Jia, Qiang Hu, Jean-Tristan Brandenburg, Li Yan, Weang-Kee Ho, Jingmei Li, José P. Miranda, Devika Godbole, Julie-Alexia Dias, Leila Dorling, Wenlong C. Chen, Nicholas Boddicker, Ying Wang, Alicia Martin, Martin J. Zhang, Yan Zhang, Joe Dennis, Esther M. John, Gabriela Torres-Mejia, Larry Kushi, Jeffrey Weitzel, Susan L. Neuhausen, Luis Carvajal-Carmona, Christopher Haiman, Elad Ziv, Laura Fejerman, Wei Zheng, Dezheng Huo, Douglas Easton, Nilanjan Chatterjee, Peter Kraft, Montserrat Garcia-Closas, Wendy Wong, Kyriaki Michailidou, Qianqian Zhu, Diptavo Dutta, Thomas U. Ahearn, Haoyu Zhang. Genetic architecture of breast cancer across diverse populations: Assessing heritability, genetic correlation, and polygenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2282.

Abstract Recurrence after surgery remains a major cause of failure in head and neck squamous cell carcinoma (HNSCC), particularly for HPV-negative patients whose 2-year failure rate is > 50%. There is unmet need for an accurate diagnostic test that predicts risk of recurrence prior to adjuvant therapy selection. We evaluated ctDNA in lymphatic exudate (“lymph”) collected via surgical drains at 24 hours to detect molecular residual disease (MRD) and compared its performance to plasma and adverse pathology features. Lymph, plasma and blood were collected from 76 HPV- HNSCC patients 24 hours after surgery. Tumor tissue was collected at surgery. 73 patients passed QC. Samples were sequenced using a 699-gene custom panel to a median of 6322x (lymph and plasma cfDNA) or 533x (tumor and blood genomic DNA). Tumor variants were directly genotyped in lymph and plasma using a tumor-informed pipeline. MRD status was determined using a calibrated cutoff based on mean variant allele fraction. Wilcoxon signed-rank test was used for comparisons. Kaplan-Meier estimator with log-rank test and Cox proportional hazards model were used for survival analysis. We previously demonstrated that 24 hour postoperative lymph ctDNA detects recurrence in HPV(-) HNSCC across two independent multi-site cohorts and by orthogonal sequencing approaches (sensitivity (SN) = 72%, specificity (SP) = 65%, p = 0.003, hazard ratio (HR) = 3.1, n = 73). When compared to other data available at this early time point (pathology and 24 hour postoperative plasma), lymph ctDNA outperformed each for recurrence detection (extranodal extension (ENE, p = 0.30), lymphovascular invasion (p = 0.02), perineural invasion (p = 0.38), positive lymph nodes (p = 0.03), plasma (p = 0.8)). We next evaluated lymph ctDNA in a critical subpopulation: patients considered intermediate risk by pathology (negative for ENE or margins but with one or more other adverse pathologic feature). Current NCCN guidelines recommend radiotherapy and to “consider systemic therapy” for these patients. Lymph ctDNA accurately stratified recurrence in this group with high sensitivity (SN = 88%, SP = 69%; P = 0.013, HR = 9.1, n = 24). Within this cohort, 77% of patients who received RT alone and later recurred were positive for lymph ctDNA at 24 hours, suggesting an opportunity to use molecular data in concert with pathology to identify patients who may benefit from adjuvant treatment intensification. Postoperative lymph represents a novel proximal analyte for MRD detection in HPV- HNSCC designed specifically for use in the immediate post-surgical window when adjuvant therapy decisions must be made. Lymph ctDNA is significantly associated with recurrence and outperforms both time-matched plasma and pathology. Accurate MRD identification at this early timepoint has the potential to augment traditional pathology and personalize adjuvant treatment paradigms in HPV-negative HNSCC. Citation Format: Seka Lazare, Zhuosheng Gu, Noah Earland, Adam Harmon, Maciej Pacula, Megan Long, Ashley Tellis, Damion Whitfield, Adam Benson, Lucien Khalil, Robert L. Ferris, Marra Francis, Aadel A. Chaudhuri, Jose P. Zevallos, Wendy Winckler. Postoperative lymphatic exudate in HPV-negative head and neck cancer detects recurrence prior to adjuvant treatment decisions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1946.

Abstract Rationale Increased risk of coronavirus disease (COVID-19) hospitalization and death has been reported among patients with clinical lung disease. Objectives To test the association of objective measures of prepandemic lung function and structure with COVID-19 outcomes in U.S. adults. Methods Prepandemic obstruction (FEV1/FVC < 0.70) and restriction (FEV1/FVC ⩾ 0.7, FVC < 80%) were defined based on the most recent spirometry exam conducted in 11 prospective U.S. general population–based cohorts. Severe obstruction was classified by FEV1 < 50%. Percentage emphysema, percentage high-attenuation areas, and interstitial lung abnormalities were defined on computed tomography in a subset. Incident COVID-19 was ascertained via questionnaires, serosurvey, and medical records from 2020 to 2023 and classified as severe (hospitalized or fatal) or nonsevere. Cause-specific hazard models were adjusted for sociodemographics, anthropometry, smoking, comorbidities, and COVID-19 vaccination status. Measurements and Main Results Among 29,323 participants (mean age, 67 yr), there were 748 severe incident COVID-19 cases over median follow-up of 17.3 months from March 1, 2020. Greater hazards of severe COVID-19 were associated with severe obstruction (vs. normal; adjusted hazard ratio [aHR], 2.11; 95% confidence interval [CI], 1.02–1.27), restriction (vs. normal; aHR, 1.40; 95% CI, 1.12–1.76), and percentage emphysema (highest vs. lowest quartile; aHR, 1.64; 95% CI, 1.03–2.61), but not greater high-attenuation areas or interstitial lung abnormalities. COVID-19 vaccination provided greater absolute risk reduction in these groups. Results were similar in participants without smoking, obesity, or clinical cardiopulmonary disease. Conclusions Prepandemic severe spirometric obstruction, spirometric restriction, and greater percentage emphysema lung on computed tomography were associated with risk of severe COVID-19. These findings support enhanced COVID-19 risk mitigation for individuals with impaired lung health and warrant further mechanistic studies on interactions of lung function, structure, and vulnerability to acute respiratory illnesses.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer. Common treatments following surgical resection include PD-1-targeting checkpoint inhibitors (pembrolizumab), as 20% of tumors are PD-L1 positive with or without systemic chemotherapy. Over the last several years, our laboratory has developed nano-immune conjugates (NIC) in which hydrophobic chemotherapy drugs like paclitaxel (PTX) and SN38, the active metabolite of irinotecan, are made water soluble by formulating them into albumin-based nanoparticles (nab) that are hydrophobically linked to various IgG1 monoclonal antibodies, creating an antigen-targetable nano-immune conjugate. To date, we have successfully tested PTX containing NICs linked to either VEGF- or CD20-targeted antibodies in two phase I clinical trials against multiple relapsed ovarian/uterine cancer or non-Hodgkin’s lymphoma, respectively. Herein, we describe a novel NIC created with either PTX or SN38 that is coated with anti-PD-L1-targeting antibodies for the treatment of a preclinical model of TNBC. In vitro testing suggests that the chemotherapy drug and antibody retain their toxicity and ligand binding capability in the context of the NIC. Furthermore, both the PTX and SN-38 NIC demonstrate superior anti-tumor efficacy relative to antibody and chemotherapy drugs alone in a PD-L1 + MDA-MB-231 human TNBC xenograft model, which could translate clinically to patients with TNBC.